This is the National Phase Application of PCT/N200/0028, filed Nov. 16, 2000.
This invention relates to a perpropanoylated glucofuranose, its preparation from glucose, and its use in the preparation of other compounds. In particular, the invention relates to crystalline 1,2,3,5,6-penta-O-propanoyl-xcex2-D-glucofuranose, a process for preparing it, and its use in the preparation of various glycosides and other compounds.
A large number of carbohydrate compounds are cheap and readily available starting materials useful in the synthesis of a wide variety of substances. One particularly desirable feature of carbohydrate compounds is that they are a source of one or more chiral carbon atoms. Many compounds useful in the pharmaceutical, agrochemical, and other industries, contain one or more chiral carbon atoms. Such compounds can be prepared in a more effective manner from carbohydrate starting materials than from non-chiral starting materials which therefore require the introduction of chirality during the synthetic route.
Examples of monosaccharide carbohydrates often used as starting materials include glucose, mannose, galactose, ribose, and arabinose. Disaccharides, for example lactose, trisaccharides, and other higher order saccharides, are also useful starting materials for the preparation of desirable compounds.
Most carbohydrate compounds contain several hydroxyl groups. Monosaccharides typically have four or five hydroxyl groups. The selective reaction of one or more of the hydroxyl groups of a monosaccharide is usually required during the synthetic route to a desired product. It is therefore often necessary to protect some or all of the hydroxyl groups of a monosaccharide in the form of ester groups, or other protecting groups.
Protection of one or more of the hydroxyl groups is often the first reaction of a sequence performed on the unprotected monosaccharide starting material.
Most readily available monosaccharide starting materials have a pyranose structure, although in solution the monosaccharide will interconvert between the pyranose form and the furanose form. The pyranose form contains a 6-membered oxygenated ring whereas the furanose form contains a 5-membered oxygenated ring. Both forms may have either an xcex1 or xcex2 orientation of the hydroxyl group at C-1.
In many instances it is useful to convert the starting material monosaccharide into a protected furanose compound. The cheapest and most readily available monosaccharide starting material is glucose. Glucose can be protected by acetylating each hydroxyl group of glucose to give peracetylated glucopyranose. Peracetylated glucopyranose can be readily prepared in one step from glucose. However, the preparation of the furanose form is less straight forward.
The preparation of peracetylated glucofuranose is known but usually requires several reaction steps and has a low overall yield of product. A common method is to constrain the glucose to the furanose form by formation of diacetone glucose. Partial hydrolysis, acetylation and subsequent acetolysis gives peracetylated glucofuranose. Another method involves the initial preparation of glucose diethyl dithioacetal followed by cyclisation in the presence of mercury salts and then acetylation.
Peracetylated glucofuranose can be also prepared from glucose in one step in the presence of a reagent such as FeCl3 or Montmorillonite clays. However, these one-step methods proceed in low yields and the products are unavoidably contaminated by significant amounts of pyranose products.
It is known to prepare perbenzoylated glucofuranose from glucose, but in several steps. For example, glucose can be treated with boric acid to give a boron complex of the glucose. The complex can be reacted with benzoyl chloride to give dibenzoylated glucose. Successive repetitions of similar procedures lead ultimately to the perbenzoylated glucofuranose.
The known methods of preparing a protected glucofuranose from an unprotected monosaccharide starting material require several reaction steps and are therefore laborious, time consuming and consequently expensive.
Additionally, a problem with many glucofuranose derivatives is that they are oils at normal temperatures and pressures, rather than crystalline solids. This means that it can be very difficult and time consuming to purify the glucofuranose. Often the xcex1- and xcex2- forms of a glucofuranose have very similar physical properties making it difficult to separate one from the other by standard methods, such as chromatography. However, if one or both of the xcex1- and xcex2- forms is crystalline, either may be readily separated from the other by recrystallisation from a suitable solvent.
Furthermore, peracylation of an unprotected saccharide typically gives a mixture of C-1 xcex1 and xcex2 products. Often only one of the xcex1 and xcex2 products is desired for further reaction. For example, a C-1 xcex2 acetate on a glucose ring can be more reactive than the C-1xcex1 counterpart towards displacement by nucleophiles due to the effect of neighbouring group participation. Thus, the comparatively mild conditions needed for the synthesis of furanosides from a C-1 xcex2 acetate can minimise any undesired anomerisation during the reaction, leading to a predominance of xcex2-furanoside product over the xcex1-furanoside form. xcex2-Furanosides are of particular synthetic interest because, for example, the nucleotides in RNA contain xcex2-furanoside moieties.
It is therefore an object of this invention to provide a novel peracylated glucofuranose, or to at least provide a useful alternative.
In a first aspect of the invention there is provided a peracylated glucofuranose which is 1,2,3,5,6-penta-O-propanoyl-xcex2-D-glucofuranose, preferably in crystalline form.
In a second aspect of the invention there is provided a process for the preparation of 1,2,3,5,6-penta-O-propanoyl-xcex2-D-glucofuranose from D-glucose. Preferably, the process includes the steps of reacting D-glucose with boric acid, or an equivalent thereof, to give a boron-glucose intermediate and reacting the intermediate with a propanoylating reagent, such as propanoic anhydride.
In a third aspect of the invention there is provided a use of 1,2,3,5,6-penta-O-propanoyl-xcex2-D-glucofuranose in the preparation of another compound, preferably a xcex2-D-glucofuranoside.
The term xe2x80x9cunprotected saccharidexe2x80x9d includes any saccharide which is fully or at least partially unprotected. Such compounds will have at least two free hydroxyl groups including the hydroxyl group at the C-1 position of the reducing-sugar residue. Generally, unprotected saccharides are fully unprotected, for example, each oxygen function at positions C-1, C-2, C-3, C-4 and C-6 of a pyranose monosaccharide will be in the form of hydroxyl groups rather than ethers, esters and the like. Unprotected saccharides may have fewer hydroxyl groups, such as 1-6 disaccharides which have the C-6 oxygen function of the reducing ring linked to a monosaccharide, for example, isomaltose, allolactose and gentiobiose.
The term xe2x80x9cperacylatedxe2x80x9d means that all hydroxyl groups of the corresponding unprotected saccharide have been converted to an ester group. The term xe2x80x9cperacetylatedxe2x80x9d therefore means that each available hydroxyl group of the unprotected saccharide has been converted to an acetate group.
The term xe2x80x9cdisaccharidexe2x80x9d refers to a compound in which two monosaccharides are joined by a glycosidic linkage. The term xe2x80x9coligosaccharidexe2x80x9d refers to those saccharides having a well-defined structure comprising a known number (greater than 2) of known monosaccharides joined by glycosidic linkages.
The term xe2x80x9creducing-sugar residuexe2x80x9d refers to the residue of a saccharide that has, in its unprotected form, a C-1 hydroxyl group and which is capable of being in an aldehydic form.
The terms xcex1 and xcex2 relate to the stereochemical arrangement of an atom or group of atoms relative to the plane of the monosaccharide ring structure. Thus, for example, a C-1 xcex1 acetate means that the acetate group lies below the plane of the carbohydrate ring whereas a C-1 xcex2 acetate means the acetate group lies above the plane of the carbohydrate ring when drawn in the conventional manner.
The compound of the invention is 1,2,3,5,6-penta-O-propanoyl-xcex2-D-glucofuranose. It has been found that the compound can be readily obtained in crystalline form. This means that purification of the compound, for example by recrystallisation, is simplified relative to the purification of non-crystalline products, for example by chromatographic techniques. It is often difficult to separate the C-1 xcex1 and xcex2 isomers of a particular compound by chromatographic techniques.
The compound 1,2,3,5,6-penta-O-propanoyl-xcex2-D-glucofuranose is obtained by treating D-glucose with boric acid in the presence of propanoic acid. A propanoylating reagent, such as propanoic anhydride, is then added to the reaction mixture. The product is obtained as a crystalline solid.
In a typical reaction of the process of the invention, glucose is treated with 2 or more mole equivalents of boric acid in propanoic acid. The reaction mixture is stirred at approximately 70xc2x0 C. for approximately one hour. Propanoic anhydride, optionally together with sulfuric acid, is added and the reaction is maintained at approximately 70xc2x0 C. while stirring for a time sufficient to give 1,2.3,5,6-penta-O-propanoyl-xcex2-D-glucofuranose.
While the process of the invention relates to the use of boric acid, it is intended that any boron reagent may be used which acts in a like manner to boric acid during the process. For example, it is envisaged that certain borate esters and salts may act as functional equivalents of boric acid during the reaction.
It is thought that the boric acid (or an equivalent thereof) complexes with the oxygen atoms at the 1- and 2- positions of the furanose form of glucose thereby stabilising that form relative to the pyranose form. Acylation then proceeds to give a predominance of the 1-xcex2 ester. Further, in the case of propanoylation of the glucose, the product is crystalline and can be readily recovered in substantially pure form from the reaction mixture.
The invention is further described with reference to the following examples which are not to be taken as limiting the invention as described.